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| Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4 |
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| Author(s): Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, Takada H, Wakeham A, Itie A, Li SY, Penninger JM, Wesche H, Ohashi PS, Mak TW, Yeh WC |
| Source: NATURE Volume: 416 Issue: 6882 Pages: 750-754 Published: APR 18 2002 |
| Times Cited: 319 References: 30 |
| Abstract: Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains(1-3). Intracellular signalling mechanisms mediated by TIRs are similar(4), with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1)(11) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M-13. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling(14,15). Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein 16, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity. |
| Document Type: Article |
| Language: English |
| Reprint Address: Yeh, WC (reprint author), Univ Toronto, Ontario Canc Inst, Amgen Inst, 620 Univ Ave,Suite 706, Toronto, ON M5G 2C1 Canada |
Addresses:
1. Univ Toronto, Ontario Canc Inst, Amgen Inst, Toronto, ON M5G 2C1 Canada
2. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1 Canada
3. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9 Canada
4. Univ Toronto, Dept Immunol, Toronto, ON M5G 2M9 Canada
5. Tularik Inc, San Francisco, CA 94080 USA |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 542FU |
| ISSN: 0028-0836 |
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